Cardiac hypertrophy occurs in response to chronic pressure and volume overload and is a frequently encountered clinical problem in patients with hypertension and valvular heart disease. Clinical and experimental work suggests that hypertrophied myocardium has a greater sensitivity than normal myocardium toward developing diastolic dysfunction in response to ischemic and hypoxia. Alterations in energy metabolism as well as impairment in calcium homeostatic mechanisms have been implicated as being responsible for these findings. The overall objectives of this research proposal are to determine if the process of hypertrophy influences the response of diastolic function to ischemia and hypoxia independent of the stress imposed to induce hypertrophy and to delineate the mechanisms responsible for this enhanced susceptibility of hypertrophied myocardium toward developing this abnormality in diastolic relaxation. Experiments will be performed in isolated buffer and blood perfused working rabbit and rat hearts at the Cardiac Muscle Research Laboratory at Boston University School of Medicine. To accomplish these objectives, the following specific aims will be addressed: 1) To determine if there are differences in the degree of diastolic dysfunction dependent upon the specific stimulus to hypertrophy, the hemodynamic response to hypoxia and ischemia will be compare among different models of pressure overload and physiologic hypertrophy. 2) To test the hypothesis that alterations in energy metabolism during the process of hypertrophy account for the greater diastolic dysfunction during ischemia and hypoxia in hypertrophied hearts. hemodynamic changes during hypoxia and ischemia will be correlated with measurements of lactate production and high energy phosphate depletion in hypertrophied and non-hypertrophied hearts. 3) To test the hypothesis that alterations in calcium handling by the process of hypertrophy contribute to this greater relaxation impairment in hypertrophied hearts, the hemodynamic response to hypoxia and ischemia will be correlated with changes in calcium transients and levels in hypertrophied and non-hypertrophied hearts using epicardial fluorescent techniques with indo-l AM as the calcium probe.